Abstract:
:Patients with non-small cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements generally respond to ALK inhibitors such as crizotinib. However, some patients with EML4-ALK rearrangements respond poorly to crizotinib. Hypoxia is involved in the resistance to chemotherapeutic treatments in several cancers, and we investigated the association between the responses to ALK inhibitors and hypoxia. Sensitivity of the H3122 NSCLC cell line (EML4-ALK rearrangement) to ALK inhibitors (crizotinib or alectinib) was investigated during a normoxic or hypoxic state using an MTT assay. We found that the cell line was resistant to the inhibitors during hypoxia. Hypoxia mediated morphologic changes, including cell scattering and the elongation of the cell shape, that are characteristic of the epithelial-mesenchymal transition (EMT). A migration assay demonstrated that the number of migrating cells increased significantly during hypoxia, compared with during normoxia. Regarding EMT-related molecules, the expressions of slug, vimentin, and fibronectin were increased while that of E-cadherin was decreased by hypoxia. In addition, hypoxia inducible factor 1A-knockdown cancelled the hypoxia-induced EMT and resistance. Our findings indicate that hypoxia induces resistance to ALK inhibitors in NSCLC with an EML4-ALK rearrangement via the EMT.
journal_name
Int J Oncoljournal_title
International journal of oncologyauthors
Kogita A,Togashi Y,Hayashi H,Sogabe S,Terashima M,De Velasco MA,Sakai K,Fujita Y,Tomida S,Takeyama Y,Okuno K,Nakagawa K,Nishio Kdoi
10.3892/ijo.2014.2574subject
Has Abstractpub_date
2014-10-01 00:00:00pages
1430-6issue
4eissn
1019-6439issn
1791-2423journal_volume
45pub_type
杂志文章abstract::Paclitaxel (PTX) is an anticancer drug currently in phase II clinical trials. This study shows for the first time that low doses of PTX (5 nM) potently induce apoptosis in human retinoblastoma Y79 cells. The effect of PTX is accompanied by a potent induction of E2F1 which appears to play a critical role in the effects...
journal_title:International journal of oncology
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doi:
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journal_title:International journal of oncology
pub_type: 杂志文章
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journal_title:International journal of oncology
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journal_title:International journal of oncology
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